权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms of Corticospinal Tract Regeneration

皮质脊髓束再生机制

基本信息

批准号：
10621552
负责人：
OSWALD STEWARD
金额：
$ 38.26万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10621552
关键词：
Adolescent Adult Animals Axon Axotomy Brain Cells Consensus Corticospinal Tracts Dendrites Development Distal Exhibits FRAP1 gene Future Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Goals Growth Human Injections Injury Intervention Label Lead Light LoxP-flanked allele Maps Microscopy Molecular Molecular Target Motor Neurons Mus Natural regeneration Nervous system structure Neurodegenerative Disorders Neuronal Injury Neurons PTEN gene Paralysed Pathway interactions Persons Phenotype Protein Biosynthesis Proteins Proto-Oncogene Proteins c-akt Rattus Recovery Regenerative response Signal Pathway Site Sorting - Cell Movement Specificity Spinal Cord Spinal cord injury Technology Testing Therapeutic Intervention Transfection Transgenic Mice Translations Visualization axon injury axon regeneration base cell growth central nervous system injury connectome genetic manipulation knock-down motor function recovery neuronal growth novel repaired response retrograde transport small hairpin RNA spinal pathway transcriptome transcriptome sequencing

项目摘要

This project is dedicated to discovering ways to induce regeneration of the corticospinal tract (CST and recovery of motor function after spinal cord injury (SCI). The CST is the pathway that is responsible for the ability to move voluntarily. Damage to the CST as a result of a spinal cord injury is the reason people are paralyzed. The project is based on discoveries that the CST can be induced to regenerate following spinal cord injury by targeting molecular pathways that control cell growth in development, specifically phosphatase and tensin homolog (PTEN). PTEN is responsible for shutting down the type of protein synthesis that is critical for cell growth during development. PTEN acts by blocking the mammalian target of Rapamycin, (mTOR), so deletion of PTEN releases inhibition on mTOR, which in turn allows the cell to synthesize proteins that are critical for cell growth. We have shown that genetic deletion of PTEN in mice and knockdown of PTEN in rats with AAVshRNA allows CST neurons to mount a robust regenerative response, which is accompanied by recovery of motor function. The new project is based on exciting and novel recent discoveries that targeting PTEN in adult nerve cells induces a state of youthful vigor in which there is perpetual growth in addition to an ability to regenerate after injury. The overall goal of the project is to determine the cellular and molecular mechanisms of this growth-enabled state and identify the genes that are turned on or shut off during growth and regeneration. Defining the pattern of gene expression that underlies the growth-enabled state in nerve cells will identify targets for future therapeutic interventions to promote regeneration and repair after injury and potentially protect nerve cells from degeneration in neurodegenerative disorders.

这个项目致力于发现诱导皮质脊髓束再生的方法 (CST以及脊髓损伤（SCI）后运动功能的恢复。科技委是一个途径，负责自主移动的能力。脊髓损伤导致的CST损伤受伤是人们瘫痪的原因。该项目是基于科学技术委员会可以通过靶向分子途径诱导脊髓损伤后再生，在发育中控制细胞生长，特别是磷酸酶和张力蛋白同源物（PTEN）。PTEN 负责关闭对细胞生长至关重要的蛋白质合成类型，发展PTEN通过阻断哺乳动物雷帕霉素靶蛋白（mTOR）发挥作用，因此缺失释放对mTOR的抑制，这反过来又允许细胞合成蛋白质，对细胞生长至关重要我们已经证明，小鼠和小鼠中PTEN基因的缺失，用AAVshRNA敲低大鼠中的PTEN允许CST神经元建立一个强大的再生反应，伴随着运动功能的恢复。新项目基于令人兴奋的新发现，靶向成人神经细胞中的PTEN诱导一种青春活力的状态，除再生能力外，还能不断生长伤后该项目的总体目标是确定细胞和分子这种生长激活状态的机制，并确定开启或关闭的基因，在生长和再生过程中。定义基因表达的模式，神经细胞的生长激活状态将确定未来治疗干预的目标，促进损伤后的再生和修复，并可能保护神经细胞免受神经退行性疾病中的变性。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Harnessing rAAV-retro for gene manipulations in multiple pathways that are interrupted after spinal cord injury.

利用RAAV-RETRO进行基因操纵，以多种脊髓损伤后中断的途径中断。

DOI：
10.1016/j.expneurol.2021.113965
发表时间：
2022-04
期刊：
EXPERIMENTAL NEUROLOGY
影响因子：
5.3
作者：
Metcalfe, Mariajose;Yee, Kelly M.;Luo, Juan;Martin-Thompson, Jacob H.;Gandhi, Sunil P.;Steward, Oswald
通讯作者：
Steward, Oswald

AAV vectors accumulate in the pineal gland after injections into the brain or spinal cord.

AAV 载体注射到大脑或脊髓后会在松果体中积聚。